a) Field of the Invention
The present invention relates to novel phenyl cyclohexanol derivatives and their pharmaceutically acceptable acid addition salts, pharmaceutical compositions and methods of use thereof as central nervous system disorder treatments.
A number of known antipsychotic drugs are disclosed in the art which have been shown to share a selective, high affinity for sigma receptors, which are sites where psychotomimetic opiates such as (+)-pentazocine and N-allylnormetazocine act. It has been suggested that the antipsychotic behavioral profile of these antipsychotic drugs can be attributed to their role as competitive antagonists of sigma receptor binding and that a systematic screen for drugs that block sigma receptors may provide a valuable strategy for identifying novel antipsychotic agents. Additionally, it has been shown that the relative potencies of these agents studied in vivo correspond well with their relative binding affinities obtained in vitro. See, for example, Snyder and Largent, J. Neuropsychiatry 1989, 1(1), 7-15; Largent et al., Clinical Neuropharmacology 1988, 11(2), 105-119; Taylor et al., Drug Development Research 1987, 11, 65-70; Ferris et al., Life Sciences 1986. 38(25), 2329-2337; and Su et al., Neuroscience Letters 1986, 71, 224-228.
The common property of neuroleptic drugs as sigma receptor ligands suggests that sigma interactions mediate some of the antipsychotic effects of neuroleptics. The distribution of sigma receptors in the limbic areas known to be involved in cognition and emotion supports this view.
b) Information Disclosure Statement
Levy et al. Comp. Rend. 191 p. 261 (1930) describes 2-dimethylamino-1-phenylcyclohexane. No utility for the compounds is disclosed.
Martin et al. U.S. Pat. No. 4,263,317, dated Apr. 21, 1981, discloses spiro[cyclohexane-1,1'(3'H)-isobenzofurans, which reportedly exhibit antidepressant, tranquilizer, analgesic and anticonvulsant activity. The patent also discloses as intermediates compounds of the formula ##STR2## wherein R.sub.5, R.sub.6 and R.sub.9 are lower-alkyl; and the geometric isomers and optical antipodes thereof; and compounds of the formula ##STR3## wherein R.sub.3 is lower-alkyl or ##STR4## wherein X is hydrogen, halogen or lower-alkyl; R.sub.5, R.sub.6 and R.sub.7 are lower-alkyl; and the geometrical isomers and optical antipodes thereof
Martin et al. U.S. Pat. No. 4,313,959, dated Feb. 2, 1982 discloses (arylmethylphenyl-aminocyclohexanols, (arylmethyl)phenyl-aminocyclohexenes and (arylmethyl)phenyl-aminocyclohexanes of the general formula ##STR5## wherein each of R and R.sub.1 is hydrogen or lower-alkyl;
R.sub.2 is hydrogen or hydroxyl; PA1 n is an integer or 0 or 1 PA1 m is an integer of 0 or 1 and when m is 0 and n is 1, the compound is a cyclohexene derivative; PA1 when m is 1, n is 0 and the compound is a cyclohexane derivative; and PA1 each of X and Y is hydrogen, halogen, alkoxy or 1 or 2 carbon atoms, lower-alkyl, hydroxy and trifluoromethyl. These compounds are said to be useful as antidepressants and anticonvulsants. PA1 R.sub.2 and R.sub.3 are the same or different lower-alkyl; or pharmaceutically acceptable salts thereof.